This invention relates to medicinal aerosol formulations and in particular to aerosol formulations containing budesoride which are suitable for administration to the respiratory system of a patient.
Pharmaceutical suspension aerosol formulations are known which use a mixture of liquid chlorofluorocarbons as the propellant. Fluorotrichloromethane, dichlorodifluoromethane and dichlorotetrafluoroethane are the most commonly used propellants in aerosol formulations for administration by inhalation.
Chlorofluorocarbons (CFCs), however, have been implicated in the destruction of the ozone layer and their production is being phased out. Hydrofluoroalkanes, such as hydrofluoroalkane 134a (HFA 134a, 1,1,1,2-tetrafluoroethane) and hydrofluoroalkane 227 (HFA 227, 1,1,1,2,3,3,3-heptafluoropropane), are viewed as being, more ozone friendly than many chlorofluorocarbon propellants; furthermrore, they have low toxicity and vapor pressures suitable for use in aerosols.
W091/04011, W091/11495, W091/1496, W093/11745, W093/11747, W094/21228, W095/15151, W096/9816, W096/9831, EP-A-0372777, EP-A-0384371, EP-A-0518600, EP-A-0518601, EP-A-0550031, EP-A-0587790 and U.S. Pat. No. 5,492,688 disclose aerosol formulations in which the propellant comprises a hydrofluoroalkane.
EP-A-0605578 discloses pharmaceutical aerosol compositions comprising a liquefied hydrofluoralkane, a powdered medicament and a polymer, soluble in the hydrofluoroalkane, having recurring structural units selected from amide containing units and carboxylic acid ester containing units. One formulation consists of HFA 227, budesonide and a polyvinylpyrrolidone/vinyl acetate copolymer and a further formulation additionally comprises polyethylene glycol.
W093/18746 discloses a pharmaceutical aerosol formulation consisting of HFA 227, budesonide, 1% by weight pol,yoxyethylene-25-glyceryl-trioleate and 1% by weight ethanol.
EP-A-0504112 discloses inter alia a formulation comprising 0.312% budesonide, 0.039% Myvacet 9-45, 1.171% Tween 60, 11.50% ethanol and 86.978% HFA 227. The ethanol content of this formulation is sufficient to dissolve a substantial proportion of the budesonide and is likely to exhibit crystal growth of budesonide particles.
W094/21229 discloses formulations comprising 0.03% particulate budesonide, 0.05% dispersing aid and 99.92% propellant which was either HFA 134a or HFA 227. The dispersing aids are derived from acetyl-oligo-L-lactic acids. The ingredients were homogenized using ultrasound. After storage, each formulation was shaken by hand then observed on standing. Each of the suspensions is said to flocculate within 5 seconds after shaking ceased.
Suspension formulations of budesonide have a propensity to rapidly form coarse flocs upon dispersion and redispersion which may deleteriously affect dosage reproducibility. There is also a tendency for budesonide to deposit from suspension onto the walls of the container.
The teaching of the state of the art does not provide a ready solution to these problems.